| Objective:With the aging process of the population,cerebral small vessel disease has become a research hotspot in the neurology department,and leukoaraiosis is a group of clinical syndromes named after imaging features in cerebral small vessel disease.Although leukoaraiosis patients are asymptomatic in the early stages,their lesions are non-benign lesions associated with clinical adverse outcomes such as dyskinesia,dementia,depression,stroke,and overall prevalence and mortality.In recent decades,scholars have carried out a large number of studies around the pathogenesis of leukoaraiosis,such as genetic factors and changes in cerebral hemodynamics,but it is still inconclusive.Many studies on genetic polymorphisms of leukoaraiosis have shown that genetic factors are also crucial to the development of leukoaraiosis.Renin-angiotensin system,including angiotensin-converting enzyme(ACE),angiotensinogen(AGT)and Angiotensin II type 1 receptor(AGTR1),can regulate blood pressure and vascular tension,and play a very important role in the formation of atherosclerosis.Many studies have shown that genetic polymorphisms of the angiotensin system are associated with cardiovascular and cerebrovascular diseases and hypertension.In addition,many scholars believe that leukoaraiosis is due to impaired cerebral vascular reserve function,intracranial hypoperfusion,and then a series of clinical manifestations.Because transcranial Doppler ultrasonography is simple and fast,many scholars use transcranial Doppler ultrasonography to observe the blood flow velocity and pulsatility index of middle cerebral artery to judge the changes and dynamic changes of intracranial arteries in patients with leukoaraiosis.It was found that the blood flow velocity of the middle cerebral artery decreased and the pulsatility index increased in patients with leukoaraiosis.Some scholars have observed the cerebral blood flow regulation function of the elderly in community by transcranial Doppler ultrasound,and discussed the relationship between the cerebral blood flow regulation function and renin angiotensin system gene polymorphism.Therefore,in order to explore the relationship between renin angiotensin system gene polymorphism and leukoaraiosis,single nucleotide polymorphisms of ACE-rs4311,rs4362,rs4461142,rs8066114,rs4646994,AGT-rs699,rs4762,AGTR1-rs5182,rs5186 were detected in patients with leukoaraiosis.It provides more theoretical basis for the pathogenesis of leukoaraiosis in genetics.In addition,the subjects in the same group were screened for breath-holding test by transcranial Doppler ultrasound to evaluate the hemodynamic changes of symptomatic leukoaraiosis patients in northern China,and to explore the relationship between breath-holding index and image performance of patients with leukoaraiosis.This study aims to reveal the pathogenesis of leukoaraiosis from the perspective of hemodynamics and gene research.Methods:This study is a cross-sectional study.From November 2016 to October2017,414 Han patients aged 43-93,including 220 males and 194 females,were enrolled in the Neurology Department of inpatient and Outpatient Clinics of the Fifth People’s Hospital of Shenyang,northern China.Patients were selected according to the strict criteria of enrollment and exclusion.According to the Fazekas grading criteria,the lesion location and degree were judged according to the manifestations of brain magnetic resonance T2 FLAIR.The patients were divided into grade 0,I,II and III.Grade 0 is no leukoaraiosis,grade I is mild leukoaraiosis(punctuate lesions),grade II is moderate leukoaraiosis(early conflunt lesions),and grade III is severe leukoaraiosis(flaky conflunt lesions).Then,according to the previously validated method,referring to the grouping criteria of Yadav,Traylor and other teams on leukoaraiosis gene research,Fazekas II and III were combined,which is equivalent to multiple lacunar infarction with conflunt white matter lesions as the case group of the ischemic leukoaraiosis,Fazekas grade 0 and grade I were combined,which is equivalent to isolated lacunar infarction(punctuate lesions)as a control group for ischemic leukoaraiosis.At the same time,try to meet the same gender,age and various factors of cerebrovascular disease in different groups to reduce the impact of various confounding factors.The single nucleotide polymorphisms of ACE-rs4311,rs4362,rs4461142,rs8066114,AGT-rs699,rs4762,AGTR1-rs5182 and rs5186 of renin angiotensin system were detected by Snapshot typing technique,and the ACE-rs46994 loci were identified by PCR.Then SPSS 24.0(IBM)software and SHEsis Online Analysis Software were used for statistical analysis.Hardy-Weinberg equilibrium test was used to analyze the frequency distribution of different genotypes and alleles in each loci in case group and control group,and linkage disequilibrium analysis and haplotype analysis were performed.Logistic stepwise regression analysis was used to assess the relationship between genotypes and alleles and the risk of leukoaraiosis.Then,suitable patients in the same group were screened for routine examination and breath-holding test with transcranial Doppler ultrasound.The blood flow velocity of the bilateral middle cerebral artery was observed before and after the breath holding for 30 seconds.The mean blood flow velocity was recorded and the breath-holding index was calculated.Then observed the relationship between clinical manifestations and image performence in patients with leukoaraiosis,and evaluated the relationship between breath-holding index and the severity of magnetic resonance image.Results:1.Among the 9 loci of renin angiotensin system,only ACE-rs4461142genotype CC,CT and TT(P=0.048)were significantly different between the case group and the control group(P<0.05).The genotypes of the other 8 loci were not statistically significant in case group and control group(P>0.05).In addition,alleles of all 9 loci were not statistically significant in case group and control group(P>0.05).2.The TT genotype of ACE-rs4362(OR=2.674,95%CI:1.267-5.649,P=0.010)was 2.674 times more likely to develop ischemic leukoaraiosis than the CC genotype after controlling for various confounding factors;and the T allele(OR=1.228,95%CI:1.038-1.454,P=0.017)was 1.228 times more likely to develop ischemic leukoaraiosis than the C allele after controlling for various confounding factors.3.The T allele of ACE-rs4461142(OR=1.190,95%CI:1.008-1.404,P=0.039)was 1.190 times more likely to develop ischemic leukoaraiosis than that of C allele.4.The T allele of AGTR1-rs5182(OR=1.527,95%CI:1.049-2.217,P=0.027)was 1.527 times more likely to develop ischemic leukoaraiosis than the C allele after controlling for various confounding factors.5.Rs4311-rs4362 was strongest linkage disequilibrium(r~2>0.6);rs4311-rs4646994,rs4362-rs4646994,rs4362-rs4461142,rs4311-rs4461142 and rs5182-rs5186 were stronger linkage disequilibrium(r~2>0.1);others were low linkage disequilibrium.6.The three haplotypes of T-A,C-A,C-C of rs5182-rs5186 had no significant difference between the case group and the control group(P>0.05).7.The image severity of leukoaraiosis was related to cognitive impairment.The more serious the image performance of leukoaraiosis,the more obvious the cognitive impairment.8.As the image performence of leukoaraiosis aggravated,the breath-holding index decreased.9.After controlling for age,coronary heart disease and stroke history,breath-holding index was still correlated with leukoaraiosis(P<0.05),independently correlated with the risk of leukoaraiosis.Conclusion:1.The TT genotype and T allele of ACE-rs4362 may increase the risk of ischemic leukoaraiosis in northern Chinese Han population.2.The T allele of ACE-rs446114 2 may increase the risk of ischemic leukoaraiosis in northern Chinese Han population.3.The T allele of AGTR1-rs5182 may increase the risk of ischemic leukoaraiosis in northern Chinese Han population.4.ACE rs4311-rs4362 is in strong linkage disequilibrium.5.The decrease of breath-holding index are independently related to leukoaraiosis in the Han population of northern China. |
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